The present invention provides methods for preparing lipid mediators related to ω-3 polyunsaturated fatty acids (PUFA), which have potential use in the development of new pharmaceuticals based on the well-established beneficial effects of PUFA.
It has long been suggested that dietary ω-3 polyunsaturated fatty acids (PUFA) (De Caterina, R., Endres, S.; Kristensen, S. D.; Schmidt, E. B., (eds). ω-3 Fatty Acids and Vascular Disease, Springer-Verlag, London. 166 pp. 1993; Gill, I., and Valivety, R. (1997), Trends in Disease, Springer-Verlag, London. 166 pp. 1993; Gill, I., and Valivety, R. (1997), Trends in Biotechnology 15, 401-409) have beneficial effects in human health and in the prevention of various diseases, including inflammation and autoimmune diseases (Simopoulos, A. P. (2002), J. Am. Coll. Nutrition 21, 495-505), rheumatoid arthritis (Cleland, L. G., James, M. J., and Proudman, S. M. (2003), Drugs 63, 845-853), cardiovascular diseases (Billman, G. E., et al. Circulation. 1999, 99, 2452; Harper, C. R., and Jacobson, T. A. (2001) Arch. Intern. Med. 161, 2185-2192), and cancer (Iigo, M. et al, Br. J. Cancer, 1997, 75, 650; Larsson, S. C., Kumlin, M., Ingelman-Sundberg, M., and Wolk, A. (2004), Am. J. Clin. Nutr. 79, 935-945).
Eicosapentaenoic acid (C20:5), the major PUFA in fish oil, was shown to form prostaglandins (PG), leukotrienes (LT) and other eicosanoids that are similar to those derived from arachidonic acid (C20:4). The different biological properties of these molecules were considered to be responsible for the role of PUFA. Despite numerous studies in this area, however, the molecular mechanisms for the actions of PUFA remain unknown.
The conversion of arachidonic acid (C20:4) to a variety of bioactive eicosanoids, including prostaglandins (PG), leukotrienes (LT) and lipoxins (LX) is well known (Nicolaou, K. C.; Ramphal, J. Y.; Petasis, N. A.; Serhan, C. N. Angew. Chem. Int. Ed. Engl. 1991, 30, 1100). It was recently demonstrated (Serhan, C. N. et al. J. Exp. Med. 2000. 192,1197) that human endothelial cells with up-regulated COX-2 treated with aspirin convert ω-3 polyunsaturated fatty acids to 18R-HEPE as well as 15R-HEPE. While 15R-HEPE led to the 5-series lipoxins (15R-LXA5), 18R-HEPE led to 5S, 12R, 18R-triHEPE (1), a novel trihydroxy-eicosanoid related to the structure of LTB4. Due to their role in the resolution of inflammation, compounds of this type were named Resolvins (Serhan, C. N.; et al, J. Exp. Med. 2002, 196,1025; Serhan, C. N. (2004) Histochem Cell Biol (2004) 122:305-321), while compound 1 was named Resolvin E1.

The formation of these trihydroxy polyunsaturated eicosanoids from PUFA suggests a novel mechanism for the therapeutic benefits of PUFA with major implications for new therapeutic approaches to a variety of diseases. Methods for the preparation of such compounds, therefore, are of great importance to the development of new therapeutic agents. Furthermore, the development of structural derivatives of these compounds may be useful for the optimization of their pharmacological profile and other desirable drug-like properties.